The present invention relates to a series of new oligopeptides which have renin-inhibitory and, hence, hypotensive activities and thus are of particular value in the diagnosis and treatment of hypertension induced by failures in the renin-angiotensin system. The invention also relates to the preparation of such compounds and to their use in such treatment.
There is considerable evidence that reduction of elevated blood pressure reduces the risks of morbidity and mortality. Elevated blood pressure (hypertension) can be caused by a variety of factors and a large number of drugs is available for the treatment of hypertension, the drug of choice being dictated in large measure by the cause of the hypertension.
Angiotensin I is a polypeptide formed by the action of renin upon a plasma protein and is converted to angiotensin II by the action of ACE (angiotensin converting enzyme). Angiotensin II causes constriction of the arterioles and can produce hypertension. Hypertension of this type can be reduced by reducing the plasma concentration of angiotensin which, in turn, can be achieved by inhibiting the activity of renin. The number of available drugs having this type of inhibitory activity is very limited, and, to date, no such drug is commercially available. A variety of peptide derivatives having this type of activity is known. Those prior art compounds believed to be closest to the compounds of the present invention, are disclosed in European Patent Publications No. 184 550, 173 481, 236 734 and 278 158.
A serious disadvantage common to almost all of the known renin-inhibitory oligopeptides, including those mentioned in the previous paragraph, is that, in practice, it is necessary to administer them by parenteral routes, e.g. by injection, as suppositories or even by inhalation. This applies even in those cases where the compounds have been suggested for oral use, since it has subsequently been found that they either are insufficiently stable to enzymes, e.g. esterases, present in the digestive system or are inadequately absorbed from the stomach and/or intestines or both. Of course, this poor stability in the digestive system is expected with oligopeptides, as the mammalian digestive system is specifically designed to break down compounds of that type. Consequently, even if the compounds can be administered orally, such high doses are necessary in order to make up for poor absorption and/or losses caused by digestion as to make oral administration impractical.
It is, of course, well known that the oral route is the preferred route of administration, particularly where (as with the drugs with which the present invention is concerned) drugs are intended for self-administration by the patient, generally over a long period of time.
Hence, the inability of the known renin-inhibitory oligopeptides to be administered via the oral route is a serious disadvantage to their practical therapeutic use, despite what may appear their useful activities.
We have now discovered a series of peptide derivatives having a very marked ability to inhibit the activity of renin, which ability is believed to be significantly better than that of the prior art compounds. However, most significantly and surprisingly, the compounds of the invention have been found to have excellent absorptive properties (especially through the intestinal and digestive tracts) upon oral administration, quite contrary to what has been generally experienced with prior art oligopeptide compounds. Moreover, certain of the compounds of the invention have additionally and unexpectedly demonstrated very good stability on oral administration (i.e. they are stable to digestive enzymes, e.g. esterases).
These unexpected properties render the compounds of the invention especially suited to oral administration, as well, of course, as to the more traditional parenteral routes of administration.
The compounds of the invention are peptides, which may be represented by the general formula (I): ##STR2## in which: A represents a single carbon-carbon bond or an alkylene group containing from 1 to 3 carbon atoms;
B represents an imino group or an alkylene group containing 1 or 2 carbon atoms; PA1 R.sup.1 represents a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group, a heterocyclic group or a group of formula (II): ##STR3## in which: R.sup.9 and R.sup.10 are independently Selected from the group consisting of hydrogen atoms, C.sub.1 -C.sub.4 alkyl groups, phenyl groups, substituted phenyl groups having at least one substituent selected from the group consisting of substituents (a), defined below, aralkyl groups, substituted aralkyl groups having at least one substituent selected from the group consisting of substituents (a), defined below, and C.sub.3 -C.sub.7 cycloalkyl groups; PA1 R.sup.2 represents a phenyl group, a substituted phenyl group having at least one substituent selected from the group consisting of substituents (a), defined below, a naphthyl group or a substituted naphthyl group having at least one substituent selected from the group consisting of substituents (a), defined below; PA1 R.sup.3 represents a thiazolyl group, an isoxazolyl group or an imidazolyl group; PA1 R.sup.4 represents an isopropyl group or a cyclohexyl group; PA1 R.sup.5 and R.sup.6 are independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, or, together with the carbon atom to which they are attached, form a C.sub.3 -C.sub.7 cycloalkyl group; PA1 R.sup.7 represents a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, or a substituted C.sub.1 -C.sub.6 alkyl group in which the substituent is selected from the group consisting of heterocyclic groups and hydroxy groups; and PA1 R.sup.8 represents a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group; PA1 said heterocyclic groups have 5 or 6 ring atoms, of which 1 or 2 are nitrogen hetero-atoms and 0 or 1 is an additional hereto-atom selected from the group consisting of sulfur and oxygen hetero-atoms, and being unsubstituted or having at least one substituent selected from the group consisting of substituents (b), defined below; PA1 said aralkyl groups are C.sub.1 -C.sub.4 alkyl groups having a phenyl or naphthyl substituent; PA1 C.sub.1 -C.sub.4 alkyl groups, halogen atoms, hydroxy groups, trifluoromethyl groups and C.sub.1 -C.sub.4 alkoxy groups; substituents (b): PA1 double bonded oxygen atoms (i.e. to form an oxo group), C.sub.1 -C.sub.4 alkyl groups, C.sub.7 -C.sub.10 aralkyl groups, substituted C.sub.7 -C.sub.10 aralkyl groups having at least one substituent selected from the group consisting of substituents (a), defined above, phenyl groups, substituted phenyl groups having at least one substituent selected from the group consisting of substituents (a), defined above, pyridyl groups, formyl groups, C.sub.2 -C.sub.5 alkylcarbonyl groups, C.sub.2 -C.sub.5 alkoxycarbonyl groups and C.sub.8 -C.sub.11 aralkyloxycarbonyl groups; PA1 the carbon atom indicated by an asterisk in the moiety of formula: ##STR4## is in the S configuration; those in which: PA1 the carbon atom indicated by an asterisk in the moiety of formula: ##STR5## is in the S configuration; those in which: PA1 the carbon atom indicated by an asterisk in the moiety of formula: ##STR6## is in the S configuration; those in which: PA1 the carbon atom indicated by an asterisk in the moiety of formula: ##STR7## is in the R configuration; those in which: PA1 the carbon atom indicated by an asterisk in the moiety of formula: ##STR8## is in the S configuration; and those in which: PA1 the carbon atom indicated by an asterisk in the moiety of formula: ##STR9## is in the S configuration. PA1 the carbon atoms indicated by an asterisk in the moiety of formula: ##STR10## are all in the S configuration. PA1 (1) A represents a single bond, and B represents a methylene group. PA1 (2) A represents a methylene group or an ethylidene group, and B represents an imino group. PA1 (3) R.sup.1 represents a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group, a non-aromatic heterocyclic group which is linked by a nitrogen atom, or a group of formula (II): ##STR11## in which: R.sup.9 and R.sup.10 are independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, phenyl groups, aralkyl groups, and C.sub.3 -C.sub.7 cycloalkyl groups; PA1 and still more preferably a morpholinyl group, a thiomorpholinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, phenyl groups, substituted phenyl groups having at least one halogen or C.sub.1 -C.sub.4 alkoxy substituent and pyridyl groups, a di(C.sub.1 -C.sub.4 alkyl)amino group, an N-(C.sub.1 -C.sub.4 alkyl)-N-benzylamino group, an N-(C.sub.1 -C.sub.4 alkyl)-N-cyclohexylamino group. PA1 (4) R.sup.2 represents a phenyl group, a 4-methoxyphenyl group or a naphthyl group. PA1 (5) R.sup.5 and R.sup.6 each represents a C.sub.1 -C.sub.4 alkyl group, or, together with the carbon atom to which they are attached, represent a cyclopentyl group or a cyclohexyl group. PA1 (6) R.sup.7 represents a C.sub.1 -C.sub..sub.6 alkyl group, or a C.sub.1 -C.sub.6 alkyl group which is substituted with a non-aromatic heterocyclic group having 5 or 6 ring atoms or with a hydroxy group and more preferably a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.4 alkyl group which is substituted with a morpholino or 2-oxo-1-pyrrolidinyl group, or a C.sub.6 alkyl group which is substituted with a hydroxy group. PA1 (7) R.sup.8 represents a hydrogen atom. PA1 A represents a single carbon-carbon bond and B represents a methylene group or A represents a methylene group and B represents an imino group; PA1 R.sup.1 represents a C.sub.1 -C.sub.4 alkyl group, a heterocyclic group or a group of formula (IIa): ##STR12## in which: R.sup.9a and R.sup.10a are independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, phenyl groups, C.sub.7 -C.sub.10 aralkyl groups and C.sub.3 -C.sub.7 cycloalkyl groups; PA1 R.sup.2 represents a phenyl group, a substituted phenol group having at least one substituent selected from the group consisting of substituents (a), defined above, or a naphthyl group; PA1 R.sup.3 represents a thiazolyl group or an isoxazolyl group; PA1 R.sup.4 represents an isopropyl group or a cyclohexyl group; PA1 R.sup.5 and R.sup.6 are independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, or, together with the carbon atom to which they are attached, form a C.sub.5 or C.sub.6 cycloalkyl group; PA1 R.sup.7 represents a C.sub.1 -C.sub.6 alkyl group, or a substituted C.sub.1 -C.sub.6 alkyl group in which the substituent is selected from the group consisting of non-aromatic heterocyclic groups and hydroxy groups; and PA1 R.sup.8 represents a hydrogen atom; PA1 A represents a single carbon-carbon bond and B represents a methylene group or A represents a methylene group and B represents an imino group; PA1 R.sup.1 represents a non-aromatic heterocyclic group or a group of formula (IIa), as defined above; PA1 R.sup.2 represents a phenyl group, a substituted phenyl group having at least one substituent selected from the group consisting of substituents (a), defined above, or a naphthyl group; PA1 R.sup.3 represents a thiazolyl group; PA1 R.sup.4 represents an isopropyl group or a cyclohexyl group; PA1 R.sup.5 and R.sup.6 are independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, or, together with the carbon atom to which they are attached, form a C.sub.5 or C.sub.6 cycloalkyl group; PA1 R.sup.7 represents a C.sub.1 -C.sub.6 alkyl group; and PA1 R.sup.8 represents a hydrogen atom; PA1 1-7. 5-{N-[N-Morpholinoacetyl-3-(1-naphthyl)alanyl]-3-(4-thiazolyl)alanyl}amino -6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-(2-methylbutyl)hexana mide, especially the (2S, 4S, 5S)-5-{N-[N-morpholinoacetyl-3-(1-naphthyl)-L-alanyl]-3-(4-thiazolyl)-L-al anyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-[2(S)-methy lbutyl]hexanamide isomer; PA1 3-4. 5-{N-[2-(1-Naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl )alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhe xanamide, especially the (2S, 4S, 5S)-5-{N-[2(R)-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-3-(4-th iazolyl)-L-alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)- N-methylhexanamide isomer; PA1 3-8. 5-{N-[2-(1-Naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl )alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-(2-methy lbutyl)hexanamide, especially the (2S, 4S, 5S)-5-{N-[2(R)-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-3-(4-th iazolyl)-L-alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)- N-[2(S)-methylbutyl]hexanamide isomer; PA1 3-34. 5-{N-[2-(1-Naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl )alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-ethylpropyl)-N-methylhe xanamide, especially the (2S, 4S, 5S)-5-{N-[ 2(R)-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl)-L -alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-ethylpropyl)-N-methylhe xanamide isomer; PA1 3-64. 5-{N-[2-Benzyl-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl)alanyl}amin o-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-butylhexanamide, especially the (2S, 4S, 5S)-5-{N-[2(R)-benzyl-3-morpholinocarbonyl)propionyl]-3-(4-thiazolyl)-L-al anyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxyl-1-methylethyl)-N-butylhexan amide isomer; PA1 3-66. 5-{N-[2-Benzyl-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl)alanyl}amin o-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-(2-methylbutyl)hexan amide, especially the (2S, 4S, 5S)-5-{N-[2(R)-benzyl-3-morpholinocarbonyl)propionyl]-3-(4-thiazolyl)-L--a lanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-[2(S)-meth ylbutyl]hexanamide isomer; PA1 3-90. 5-{N-[2-Benzyl-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl)alanyl}amin o-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide, especially the (2S, 4S, 5S)-5-{N-[2(R)-benzyl-3-morpholinocarbonyl)propionyl]-3-(4-thiazolyl)-L-al anyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexan amide isomer; PA1 3-91. 5-{N-[2-Benzyl-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl)alanyl}amin o-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-ethylhexanamide, especially the (2S, 4S, 5S)-5-{N-[2(R)-benzyl-3-morpholinocarbonyl)propionyl]-3-(4-thiazolyl)-L-al anyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxyl-1-methylethyl)-N-ethylhexan amide isomer; PA1 3-97. 5-{N-[2-Benzyl-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl)alanyl}amin o-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-ethylpropyl)-N-methylhexanamide, especially the (2S, 4S, 5S)-5-{N-[2(R)-benzyl-3-morpholinocarbonyl)propionyl]-3-(4-thiazolyl)-L-al anyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-ethylpropyl)-N-methylhexan amide isomer; PA1 3-112. 5-{N-[2-Benzyl-3-(N-benzyl-N-methylcarbamoyl)propionyl]-3-(4-thiazolyl)ala nyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexana mide, especially the (2S, 4S, 5S)-5-{N-[2(R)-benzyl-3-(N-benzyl-N-methylcarbamoyl)propionyl]-3-(4-thiazo lyl)-L-alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-me thylhexanamide isomer; PA1 3-114. 5-{N-[2-Benzyl-3-(N-cyclohexyl-N-methylcarbamoyl)propionyl]-3-(4-thiazolyl )alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhe xanamide, especially the (2S, 4S, 5S)-5-{N-[2(R)-benzyl-3-(N-cyclohexyl-N-methylcarbamoyl)propionyl]-3-(4-th iazolyl)-L-alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)- N-methylhexanamide isomer; PA1 3-152. 5-{N-[2-(p-Methoxybenzyl)-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl) alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhex anamide, especially the (2S, 4S, 5S)-5-{N-[2(R)-(p-methoxybenzyl)-3-morpholinocarbonyl)propionyl]-3-(4-thia zolyl)-L-alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N- methylhexanamide isomer; and PA1 6-20. 5-{N-[2-(1-Naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl )alanyl}amino- 6-cyclohexyl-4-hydroxy-2-(1-hydroxycyclohexyl)-N-methylhexanamide, especially the (2S, 4S, 5S)-5-{N-[2(R-)-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-3-(4-t hiazolyl)-L-alanyl}amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxycyclohexyl)-N-m ethylhexanamide isomer; PA1 A' represents a C.sub.1 -C.sub.3 alkylene group; and PA1 R.sup.1a represents any one of the groups defined above for R.sup.1 except that, where R.sup.1 represents an imino (--NH--) or amino group, this is protected. PA1 R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined above; PA1 Boc represents a t-butoxycarbonyl group; and PA1 R.sup.b represents a lower, e.g. C.sub.1 -C.sub.4, alkyl group. PA1 R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and Boc are as defined above; and PA1 R.sup.c represents an aralkyl group. PA1 R.sup.2 is as defined above; PA1 R.sup.1b represents any one of the groups defined for R.sup.1a other than a lower alkyl group or a lower alkoxy group, i.e. it represents a heterocyclic group or said group of formula (II); PA1 n is the integer 1 or 2; PA1 R.sup.11 represents a lower, e.g. C.sub.1 -C.sub.4, alkyl group or an aralkyl group; PA1 R.sup.12 represents a phenyl group or a lower, e.g. C.sub.1 -C.sub.4, alkyl group; and PA1 X represents a halogen atom. PA1 R.sup.3, R.sup.11 and X are as defined above; and PA1 R.sup.13 represents an aliphatic acyl group, such as an acetyl, propionyl or butyryl group.
substituents (a):
and pharmaceutically acceptable salts thereof.
The invention also provides a method for the treatment or prophylaxis of angiotensin-induced hypertension in an animal, especially a mammal, which may be human or non-human, by the administration thereto of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The invention also provides a composition for the treatment of angiotensin-induced hypertension in an animal, especially a mammal, which may be human or non-human, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier or diluent.
The compounds of the invention may be prepared by reacting together two compounds, one having a terminal carboxy group or reactive derivative thereof and the other having a terminal amino group or reactive derivative thereof, under conditions conventional for peptide synthesis, said two compounds corresponding to the fragments derivable by cleavage of any one of the peptide bonds in said compound of formula (I). Preferred methods of preparing the compounds are described in greater detail hereafter.